Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Low-dose naltrexone is used to treat fibromyalgia despite minimal evidence for its efficacy. This trial aimed to investigate whether 12-week treatment with 6 mg low-dose naltrexone was superior to placebo for reducing pain in women with fibromyalgia. METHODS: We did a single-centre, randomised, double-blind, placebo-controlled trial in Denmark. We enrolled women aged 18-64 years who were diagnosed with fibromyalgia. Participants were randomly assigned 1:1 to receive low-dose naltrexone (6 mg) or an identical-appearing placebo, using a computerised algorithm with no stratifications applied. Participants, investigators, outcome assessors, and statistical analysts were all masked to treatment allocation. The primary outcome was change in pain intensity on an 11-point numeric rating scale from baseline to week 12, in the intention-to-treat population. Safety was assessed in participants in the intention-to-treat population who received at least one dose of their allocated intervention. This trial was registered with ClincalTrials.gov (NCT04270877) and EudraCT (2019-000702-30). FINDINGS: We screened 158 participants for eligibility from Jan 6, 2021, to Dec 27, 2022, and 99 patients were randomly assigned to low-dose naltrexone (n=49) or placebo (n=50). The mean age was 50·6 years (SD 8·8), one (1%) of 99 participants was Arctic Asian and 98 (99%) were White. No participants were lost to follow-up. The mean change in pain intensity was -1·3 points (95% CI -1·7 to -0·8) in the low-dose naltrexone group and -0·9 (-1·4 to -0·5) in the placebo group, corresponding to a between-group difference of -0·34 (-0·95 to 0·27; p=0·27, Cohen's d 0·23). Discontinuations due to adverse events were four (8%) of 49 in the low-dose naltrexone group and three (6%) of 50 in the placebo group. 41 (84%) of 49 patients in the low-dose naltrexone group had an adverse event versus 43 (86%) of 50 in the placebo group. One serious adverse event occurred in the placebo group and no deaths occurred. INTERPRETATION: This study did not show that treatment with low-dose naltrexone was superior to placebo in relieving pain. Our results indicate that low-dose naltrexone might improve memory problems associated with fibromyalgia, and we suggest that future trials investigate this further. FUNDING: The Danish Rheumatism Association, Odense University Hospital, Danielsen's Foundation, and the Oak Foundation.

Epidural analgesia versus oral morphine for postoperative pain management following video-assisted thoracic surgery: A randomised, controlled, double-blind trial.

BACKGROUND: The use of thoracic epidural analgesia for postoperative pain management in video-assisted thoracic surgery (VATS) is controversial. Still, the evidence on omitting it in favour of systemic opioids is inconclusive, and studies are small and non-blinded. OBJECTIVE: We aimed to compare pain after VATS using epidural analgesia or enteral opioids for postoperative pain management. DESIGN/SETTING/PATIENTS/INTERVENTION: A randomised, double-blind, controlled trial at a Danish tertiary hospital. Adult patients scheduled for VATS were assigned to multimodal non-opioid baseline analgesia supplemented with either thoracic epidural analgesia (TE Group) or oral morphine (OM Group) for postoperative pain management. We recorded pain five times a day, both at rest and during activity, using the Numeric Rating Scale (NRS) and categorised it into "acceptable pain" or "unacceptable pain". Unacceptable pain was defined as NRS (at rest) ≥3 or NRS (with activity) ≥5 when supplementary analgesics were given. MAIN OUTCOME MEASURES: The primary outcomes were the proportions of patients experiencing "unacceptable pain" during the postoperative period and the use of intravenous "rescue" opioids. RESULTS: Of the 161 included patients, 146 received the allocated treatment and their data were analysed. At rest, 34% of patients in the TE Group and 64% of patients in the OM Group experienced unacceptable pain during the study period, a significant between-group difference of 30% ( P  < 0.0005). During activity these percentages were 32% of patients in the TE Group and 59% in the OM group, a difference of 27% ( P  < 0.005). The median intravenous rescue morphine consumption during the study period was 4.5 [interquartile range (IQR), 0-10.0] mg in the TE Group and 7.5 [0-19.0] mg in the OM Group ( P  < 0.005). CONCLUSION: Epidural analgesia provided better pain relief after VATS than oral morphine. The between-group difference in rescue intravenous morphine consumption was statistically significant but clinically irrelevant. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02359175).

The Danish Pain Research Biobank (DANPAIN-Biobank): a collection of blood, cerebrospinal fluid, and clinical data for the study of neuroimmune and glia-related biomarkers of chronic pain.

Background: Chronic pain is a major health problem worldwide but the limited knowledge of its underlying pathophysiology impairs the opportunities for diagnostics and treatment. Biomarkers of chronic pain are greatly needed to understand the disease and develop new targets for interventions and drug treatments, and potentially introduce more precise diagnostic procedures. Much evidence points to a neuroimmune pathology for many chronic pain conditions and that important neuroimmune biomarkers exist in the cerebrospinal fluid (CSF) of patients with chronic pain. Systematic collection of CSF in large cohorts of chronic pain patients and healthy volunteers has proven difficult, however. We established the Danish Pain Research Biobank (DANPAIN-Biobank) with the aim of studying potential neuroimmune and glia-related biomarkers of chronic pain. In this paper, we describe the methods and the study population of the DANPAIN-Biobank. Methods: In this cross-sectional study, we included (I) participants with high-impact (HI) chronic pain from a tertiary, interdisciplinary pain center; (II) participants with osteoarthritic pain scheduled for arthroplasty surgery of the hip or knee at a regional hospital; and (III) pain-free volunteers. All participants completed a questionnaire assessing pain, functional impairment, anxiety, depression, and insomnia before samples of blood and CSF were extracted. Quantitative sensory tests were performed on participants with HI chronic pain and pain-free volunteers, and postoperative outcome scores were available on participants with osteoarthritic pain. Results: Of the 352 participants included, 201 had HI chronic pain (of which 71% had chronic widespread pain), 81 had chronic osteoarthritic pain, and 70 were pain-free volunteers. Samples were handled uniformly, and CSF samples were frozen within 30 minutes. Conclusions: We describe the content of the DANPAIN-Biobank, which is unique in terms of the number of participants (including pain-free volunteers), extensive clinical data, and uniformity in sample handling. We believe it presents a promising new platform for the study of neuroimmune and glia-related biomarkers of chronic pain.

Early Pre- and Postoperative Enteral Nutrition and Growth in Infants with Symptomatic Congenital Diaphragmatic Hernia.

OBJECTIVES: Nutritional support during the neonatal and postoperative period in congenital diaphragmatic hernia (CDH) is challenging and controversial. We aimed to report on early enteral nutritional support in symptomatic CDH patients during the pre- and postoperative period, including feasibility, associated factors with established full enteral nutrition, and weight at birth, discharge, and 18 months. METHODS: We retrospectively collected data on nutrition: type and volume of enteral nutrition and parental support. Enteral feeding was introduced preoperatively from day 1 after birth, increased step-wised (breastmilk preferred), and resumed after CDH repair on the first postoperative day. Baseline data were available from our CDH database. RESULTS: From 2011 to 2020, we identified 45 CDH infants. Twenty-two were girls (51.1%), 35 left sided (77.8%), and 40 underwent CDH repair (88.9%). Median (interquartile range) length of stay in the pediatric intensive care unit was 14.6 days (6.0-26.5), and 1-year mortality was 17.8%.Postoperatively, 120 and 160 mL/kg/d of enteral nutrition was achieved after a median of 6.5 (3.6-12.6) and 10.6 (7.6-21.7) days, respectively. In total, 31 (68.9%) needed supplemental parenteral nutrition in a median period of 8 days (5-18), and of those 11 had parenteral nutrition initiated before CDH repair. No complications to enteral feeding were reported. CONCLUSION: Early enteral nutrition in CDH infants is feasible and may have the potential to reduce the need for parental nutrition and reduce time to full enteral nutrition in the postoperative period.

Associations between clinical interventions and transcutaneous blood gas values in postoperative patients.

PURPOSE: Postoperative monitoring of circulation and respiration is pivotal to guide intervention strategies and ensure patient outcomes. Transcutaneous blood gas monitoring (TCM) may allow for noninvasive assessment of changes in cardiopulmonary function after surgery, including a more direct assessment of local micro-perfusion and metabolism. To form the basis for studies assessing the clinical impact of TCM complication detection and goal-directed-therapy, we examined the association between clinical interventions in the postoperative period and changes in transcutaneous blood gasses. METHODS: Two-hundred adult patients who have had major surgery were enrolled prospectively and monitored with transcutaneous blood gas measurements (oxygen (TcPO2) and carbon dioxide (TcPCO2)) for 2 h in the post anaesthesia care unit, with recording of all clinical interventions. The primary outcome was changes in TcPO2, secondarily TcPCO2, from 5 min before a clinical intervention versus 5 min after, analysed with paired t-test. RESULTS: Data from 190 patients with 686 interventions were analysed. During clinical interventions, a mean change in TcPO2 of 0.99 mmHg (95% CI-1.79-0.2, p = 0.015) and TcPCO2 of-0.67 mmHg (95% CI 0.36-0.98, p < 0.001) was detected. CONCLUSION: Clinical interventions resulted in significant changes in transcutaneous oxygen and carbon dioxide. These findings suggest future studies to assess the clinical value of changes in transcutaneous PO2 and PCO2 in a postoperative setting. TRIAL REGISTRY: Clinical trial number: NCT04735380. CLINICAL TRIAL REGISTRY: https://clinicaltrials.gov/ct2/show/NCT04735380.

Procedural Aspects of Epidural Catheter Placement: A Prospective Observational Study of 173 Epidural Catheter Insertions.

OBJECTIVE: The risks and benefits of epidural analgesia have been studied extensively, but information regarding many other aspects of epidural catheter insertion is limited. The authors aimed to add information regarding procedural pain, procedure duration, failure rates, and the effect of experience to the ongoing discussion on this procedure. DESIGN: A prospective observational study. SETTING: A Danish tertiary hospital. PARTICIPANTS: Patients scheduled to undergo video-assisted thoracic surgery. INTERVENTIONS: Epidural catheter insertion in 173 patients undergoing video-assisted thoracic surgery for lung cancer. MEASUREMENTS AND MAIN RESULTS: The authors recorded the time required for the epidural insertion procedure, the attempts used, insertion level, access use, patient position, placement technique used, and the designation of the physician placing the catheter. Furthermore, the authors asked the patients to evaluate the expected procedural pain, and after the procedure the authors asked them to evaluate the actual level of pain experienced. Six and 24 months after discharge, the authors examined persistent sequelae by using questionnaire assessments. The median procedure duration was 13 minutes, with 75% of the catheters placed within 22 minutes. Actual procedure-related pain (mean score [M] = 3.5, SD = 2.0) was significantly (p < 0.0001) less than that expected before the procedure (M = 4.9, SD = 2.0). The patients' expected pain, attempts required for successful catheter placement, and approach used to access the epidural space significantly affected the actual procedure-related pain (p = 0.001, p ≤ 0.003, and p = 0.023, respectively). Persistent pain and sensory disturbances were observed in 11% and 4% of the patients, respectively, after 6 months and in 6% and 4% of the patients, respectively, after 2 years. CONCLUSIONS: In this study, the authors examined several lesser-known aspects of epidural procedures. The use of epidural analgesia as part of the pain management plan after surgery requires a more complex evaluation instead of merely discussing the possibility of procedural infections, hematomas, or neurologic injuries. The procedure time, patients' expected and experienced pain related to the procedure, and the potential long-term side effects should be a part of the decision-making process.

Vacuum-assisted closure versus on-demand relaparotomy in patients with secondary peritonitis-the VACOR trial: protocol for a randomised controlled trial.

BACKGROUND: Secondary peritonitis is a severe condition with a 20-32% reported mortality. The accepted treatment modalities are vacuum-assisted closure (VAC) or primary closure with relaparotomy on-demand (ROD). However, no randomised controlled trial has been completed to compare the two methods potential benefits and disadvantages. METHODS: This study will be a randomised controlled multicentre trial, including patients aged 18 years or older with purulent or faecal peritonitis confined to at least two of the four abdominal quadrants originating from the small intestine, colon, or rectum. Randomisation will be web-based to either primary closure with ROD or VAC in blocks of 2, 4, and 6. The primary endpoint is peritonitis-related complications within 30 or 90 days and one year after index operation. Secondary outcomes are comprehensive complication index (CCI) and mortality after 30 or 90 days and one year; quality of life assessment by (SF-36) after three and 12 months, the development of incisional hernia after 12 months assessed by clinical examination and CT-scanning and healthcare resource utilisation. With an estimated superiority of 15% in the primary outcome for VAC, 340 patients must be included. Hospitals in Denmark and Europe will be invited to participate. DISCUSSION: There is no robust evidence for choosing either open abdomen with VAC treatment or primary closure with relaparotomy on-demand in patients with secondary peritonitis. The present study has the potential to answer this important clinical question. TRIAL REGISTRATION: The study protocol has been registered at clinicaltrials.gov (NCT03932461). Protocol version 1.0, 9 January 2022.

Performance of the 2016 diagnostic criteria for fibromyalgia in a tertiary care pain rehabilitation setting: a diagnostic accuracy study

OBJECTIVES: With the International Classification of Diseases 11th revision (classifying fibromyalgia as a primary pain disorder) soon to be implemented, the importance of pain physicians being able to identify patients with fibromyalgia is emphasized. The diagnostic criteria proposed in 2016 are based on self-reported pain distribution and symptom severity. The study aimed to evaluate the diagnostic accuracy of the 2016 diagnostic criteria for fibromyalgia applied in a population of patients with high impact chronic pain referred for pain rehabilitation. METHODS: The study was performed as a diagnostic accuracy study at two Danish interdisciplinary pain rehabilitation centers, including 215 participants. All participants were evaluated clinically to identify patients with fibromyalgia. The diagnosis was based on expert opinion, but the minimum requirements were: (1) pain in all four body quadrants and axially for at least three months and (2) minimum 8 of 18 positive tender points. Participants filled in the fibromyalgia survey questionnaire, the patient version of the 2016 diagnostic criteria. Sensitivity, specificity, likelihood ratios, and positive and negative post-test probabilities were calculated using a clinical diagnosis of fibromyalgia as the reference standard. RESULTS: Based on clinical diagnosis 45% of the participants were diagnosed with fibromyalgia; of these, only 19% had been diagnosed previously. The 2016 diagnostic criteria demonstrated a sensitivity of 88.5%, a specificity of 81.5%, a positive likelihood ratio of 4.79, a negative likelihood ratio of 0.14, a positive post-test probability of 79.4%, and a negative post-test probability of 10.2%. CONCLUSIONS: Fibromyalgia was severely under-diagnosed among patients with high impact chronic pain referred to tertiary care in two pain rehabilitation centers in Denmark. The 2016 diagnostic criteria showed sufficient discriminatory properties suggesting that the fibromyalgia survey questionnaire can be used as a screening tool assisting the identification of fibromyalgia in this patient population.

Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Low-dose naltrexone (LDN) is used widely as an off-label treatment for pain despite limited evidence for its effectiveness. A few small trials with a high risk of bias have investigated the effect of LDN on pain associated with fibromyalgia in women, but larger and more methodologically robust studies are needed. The primary aim of this randomized controlled trial is to investigate if 12 weeks of LDN treatment is superior to placebo in reducing the average pain intensity during the last 7 days in women with fibromyalgia. METHODS: A single-center, permuted block randomized, double-blind, placebo-controlled, parallel-group trial will be performed in Denmark. Randomization comprises 100 women aged 18-64 years diagnosed with fibromyalgia who will be treated with either LDN or placebo for 12 weeks including a 4-week titration phase. The primary outcome is change in average pain intensity (during the last 7 days) from baseline to 12 weeks. Secondary outcomes are other fibromyalgia-related symptoms, i.e., tenderness, fatigue, sleep disturbance, stiffness, memory problems, depression, anxiety and measures of global assessment, physical function, impact of fibromyalgia, pain distribution, and health-related quality of life. Intention-to-treat analysis will be performed, and the number of responders with a more than 15%, 30%, and 50% improvement of pain after 12 weeks will be calculated for the LDN and placebo groups. Exploratory outcomes include measures of pain sensitivity, muscle performance, and biomarkers. DISCUSSION: This study will contribute with high-level evidence on the efficacy of low-dose naltrexone for the treatment of pain in women with fibromyalgia. Secondary outcomes include both disease-specific and generic components investigating whether LDN influences other symptoms than pain. Explorative outcomes are included to provide greater insight into the mechanism of action of LDN and possibly a better understanding of the underlying pathology in fibromyalgia. TRIAL REGISTRATION: EudraCT 2019-000702-30. Registered on 12 July 2019. ClinicalTrials.gov NCT04270877. Registered on 17 February 2020.

The effect of pre-analytical handling on the stability of fractalkine, monocyte chemoattractant protein 1 (MCP1), interleukin 6 and interleukin 8 in samples of human cerebrospinal fluid.

Cytokine networks in cerebrospinal fluid (CSF) are important to our understanding of several neuroinflammatory diseases. Knowledge about optimal handling of samples is limited but important to minimize bias and reduce costs in CSF biomarker studies. The aim of this study was to examine the effect of storage temperature and time delay from CSF sample collection until freezing on the concentration of 11 different cytokines thought to be associated with chronic pain. CSF samples from 21 individuals undergoing hip or knee arthroplasty under spinal anesthesia were divided between two tubes. One tube was stored and centrifuged (within 30 min) at room temperature, and one tube was stored in ice water and centrifuged (within 30 min) at 4 °C. Each tube was split into six vials that were frozen at -80 °C, 0.5, 1, 2, 3, 4, or 5 h after collection. Cytokines were analyzed using a multiplex panel. A random effect panel data regression was conducted for each biomarker including the variables of storage temperature until freezing and time delay. Four cytokines had detectable levels: Fractalkine, monocyte chemoattractant protein 1(MCP-1), interleukine 6 (IL-6), and interleukine 8 (IL-8). There was no significant effect of storage temperature and time delay on MCP-1, IL-6, or IL-8 concentrations. Fractalkine concentration showed no clear trend. No concentration differences were observed between samples kept in ice water and those at room temperature except at the 3-h time point, and there was no overall significant effect of time delay on fractalkine concentration. We found no clear effect of storage temperature and time delay up to five hours from sample collection until freezing on the CSF concentrations of fractalkine, MCP-1, IL-6, or IL-8.

Urine neutrophil gelatinase-associated lipocalin and urine output as predictors of the successful discontinuation of continuous renal replacement therapy in critically ill patients with acute kidney injury.

BACKGROUND: Continuous renal replacement therapy (CCRT) is a frequently used modality for the support of intensive care patients with acute kidney injury (AKI). Nevertheless, there are no objective criteria for the discontinuation of CRRT. The purpose of this study was to investigate whether urine neutrophil gelatinase-associated lipocalin (uNGAL) alone or in combination with urine output could be used as a diagnostic test for renal function recovery in ICU patients on CRRT. METHODS: This was a single-centre prospective observational study including patients with acute kidney failure needing CRRT. Sixty-nine patients were enrolled, and 54 completed the study. Of the 54 patients, 22 recovered renal function (REC), defined as dialysis independency at 72 h from discontinuation, while 32 patients did not (NREC). Urine NGAL was measured at 0, 6, 12, and 24 h after CRRT discontinuation. The cumulated urine output was measured for 24 h prior to discontinuation and at 6, 12, and 24 h after discontinuation. Missing uNGAL values were calculated by interpolation. The Youden's index was used to calculate cut-off values in order to define uNGAL and urine output single variable and 2-variable diagnostic tests with the optimum prediction of successful CRRT discontinuation. RESULTS: Baseline characteristics at CRRT initiation were similar between groups. Compared to the NREC group, the REC group had significantly higher urine output (p < 0.0001) and lower uNGAL (p < 0.001) at all time points, except for uNGAL at 24 h (p < 0.24). The best uNGAL predictor for successful CRRT discontinuation was uNGAL at 6 h after discontinuation (predictive value 80%). The best single predictor was cumulated urine output 24 h before discontinuation (predictive value 85%). The combinations of uNGAL at 6 h (cut-off 1650 µg/L) with cumulated urine output 24 h prior to discontinuation (cut-off 210 ml) proved to be the superior tests (using either "or" or "and"), with predictive values of 93% (successful CRRT discontinuation) and 92% (dialysis dependency). CONCLUSIONS: With a predictive value of 93%, the combination of uNGAL at 6 h after and the cumulated urine output 24 h prior to CRRT cessation proved to be the best diagnostic test for successful CRRT discontinuation in ICU patients. CLINICAL TRIAL REGISTRATION: N/A.

Congenital diaphragmatic hernia presenting with symptoms within the first day of life; outcomes from a non-ECMO centre in Denmark.

BACKGROUND: Between 1998 and 2015, we report on the survival of congenital diaphragmatic hernia (CDH)-infants presenting with symptoms within the first 24 h of life, treated at Odense University Hospital (OUH), a tertiary referral non-extracorporeal membrane oxygenation (ECMO) hospital for paediatric surgery. METHODS: We performed a retrospective cohort study of prospectively identified CDH-infants at our centre. Data from medical records and critical information systems were obtained. Baseline data included mode of delivery and infant condition. Outcome data included 24-h, 28-day, and 1 year mortality rates and management data included intensive care treatment, length of stay in the intensive care unit, time of discharge from hospital, and surgical intervention. Descriptive analyses were performed for all variables. Survivors and non-survivors were compared for baseline and treatment data. RESULTS: Ninety-five infants were identified (44% female). Of these, 77% were left-sided hernias, 52% were diagnosed prenatally, and 6.4% had concurrent malformations. The 28-day mortality rate was 21.1%, and the 1 year mortality rate was 22.1%. Of the 21 non-survivors, nine died within the first 24 h, and 10 were sufficiently stabilised to undergo surgery. A statistically significant difference was observed between survivors and non-survivors regarding APGAR score at 1 and 5 min., prenatal diagnosis, body length at birth, and delivery at OUH. CONCLUSIONS: Our outcome results were comparable to published data from other centres, including centres using ECMO.

Low-Dose Naltrexone for the Treatment of Fibromyalgia: Investigation of Dose-Response Relationships.

OBJECTIVE: This study explores dose-response relationships when treating fibromyalgia with low-dose naltrexone. DESIGN: A single-blinded clinical trial was carried out using the "up-and-down" method. SUBJECTS: Subjects included women with a diagnosis of fibromyalgia aged 18-60 years who had been referred to treatment at a public pain clinic at a Danish university hospital. METHODS: The test doses were in the range 0.75-6 mg, and the dosing interval was 0.75 mg. The method was sequential and allowed predicting the dose effective in 50% (ED50) and 95% (ED95) of the subjects when the dose had shifted direction 10 times, and six pairs of "up-and-down" data were available. RESULTS: A total of 27 subjects were included in the study; two subjects were withdrawn. After inclusion of 25 evaluable subjects, the dose estimates were calculated as 3.88 mg for ED50 and 5.40 mg for ED95. As a secondary outcome, the effects on 10 common fibromyalgia symptoms were evaluated. A high interindividual variation was observed both in the symptom presentation at baseline and in which symptoms were reduced by low-dose naltrexone. CONCLUSIONS: This study is the first to explore dose-response relationships in the treatment of fibromyalgia with low-dose naltrexone. Future placebo-controlled randomized clinical trials are needed, and according to our findings, 4.5 mg, which has previously been used, seems to be a relevant test dose. We recommend that future studies include additional nonpain fibromyalgia symptoms as outcome measures.

Moderately prolonged permissive hypotension results in reversible metabolic perturbation evaluated by intracerebral microdialysis - an experimental animal study.

BACKGROUND: Damage control resuscitation (DCR) and damage control surgery (DCS) is the main strategy in patients with uncontrollable hemorrhagic shock. One aspect of DCR is permissive hypotension. However, the duration of hypotension that can be tolerated without affecting the brain is unknown. In the present study we investigate the effect of 60 min severe hypotension on the brain's energy metabolism and seek to verify earlier findings that venous cerebral blood can be used as a marker of global cerebral energy state. MATERIAL AND METHODS: Ten pigs were anaesthetized, and vital parameters recorded. Microdialysis catheters were placed in the left parietal lobe, femoral artery, and superior sagittal sinus for analysis of lactate, pyruvate, glucose, glycerol, and glutamate. Hemorrhagic shock was induced by bleeding the animal until mean arterial pressure (MAP) of 40 mmHg was achieved. After 60 min the pigs were resuscitated with autologous blood and observed for 3 h. RESULTS: At baseline the lactate to pyruvate ratios (LP ratio) in the hemisphere, artery, and sagittal sinus were (median (interquartile range)) 13 (8-16), 21 (18-24), and 9 (6-22), respectively. After induction of hemorrhagic shock, the LP ratio from the left hemisphere in 9 pigs increased to levels indicating a reversible perturbation of cerebral energy metabolism 19 (12-30). The same pattern was seen in LP measurements from the femoral artery 28 (20-35) and sagittal sinus 22 (19-26). At the end of the experiment hemisphere, artery and sinus LP ratios were 16 (10-23), 17 (15-25), and 17 (10-27), respectively. Although hemisphere and sinus LP ratios decreased, they did not reach baseline levels (p < 0.05). In one pig hemisphere LP ratio increased to a level indicating irreversible metabolic perturbation (LP ratio > 200). CONCLUSION: During 60 min of severe hypotension intracerebral microdialysis shows signs of perturbations of cerebral energy metabolism, and these changes trend towards baseline values after resuscitation. Sagittal sinus microdialysis values followed hemisphere values but were not distinguishable from systemic arterial values. Venous (jugular bulb) microdialysis might have a place in monitoring conditions where global cerebral ischemia is a risk.

From acute to chronic pain after thoracic surgery: the significance of different components of the acute pain response.

PURPOSE: Acute postoperative pain is a strong predictor for postthoracotomy pain syndrome (PTPS), but the mechanism is unknown. Even though thoracic pain is usually considered the dominating acute pain after thoracic surgery, up to 45% of patients consider shoulder pain to be dominating pain and often this shoulder pain is referred visceral pain. This study aims to examine which components of the acute pain response after thoracic surgery were associated with PTPS and if any signs of a generalized central hypersensitivity could be identified in patients with PTPS. PATIENTS AND METHODS: In a prospective cohort study, 60 consecutive patients for lobectomy were included and examined preoperatively and 12 months postoperatively for pain and signs of hypersensitivity using a comprehensive protocol for quantitative sensory testing. Thoracic pain, shoulder pain, referred pain, and overall pain were assessed five times daily during the first four postoperative days. RESULTS: Sixteen patients (31% of the 52 patients who completed the study) developed PTPS. Thoracic pain was the only pain component that was associated with PTPS and was a stronger predictor for PTPS than overall pain. There were no signs of hypersensitivity before or after the operation in patients with PTPS, but patients with PTPS more often suffered from preoperative pain. CONCLUSION: Thoracic pain was the only component of the acute pain response that predicted PTPS and was a stronger predictor than overall pain.

Bedside Monitoring of Cerebral Energy State During Cardiac Surgery-A Novel Approach Utilizing Intravenous Microdialysis.

OBJECTIVES: This study investigated whether the lactate-to-pyruvate (LP) ratio obtained by microdialysis (MD) of the cerebral venous outflow reflected a derangement of global cerebral energy state during cardiopulmonary bypass (CPB). DESIGN: Interventional, prospective, randomized study. SETTING: Single-center, university teaching hospital. PARTICIPANTS: The study included 10 patients undergoing primary, elective coronary artery bypass grafting. INTERVENTIONS: Patients were randomized blindly to low mean arterial pressure (MAP) (40-60 mmHg; n = 5) or high MAP (60-80 mmHg; n = 5) during CPB. The MD catheters were positioned in a retrograde direction into the jugular bulb, and a reference catheter was inserted into the brachial artery. The correlations among LP ratio, MAP, data obtained from bifrontal near-infrared spectroscopy (NIRS), and postoperative neurologic outcome measures were assessed. MEASUREMENTS AND MAIN RESULTS: The correlated difference between pooled LP ratio (low and high MAP) of the jugular venous and the arterial blood was significant (LParterial 17 [15-20] v LPvenous 26 [23-27]; p = 0.0001). No cerebral desaturations (decrease in rSO2>20% from baseline) were observed in either group during CPB. In each group, 50% of the patients showed significant cognitive decline (mini-mental state examination, 3 points) 2 days after surgery. CONCLUSION: The LP ratio of cerebral venous blood increased significantly during CPB, indicating compromised cerebral oxidative metabolism. Conventional monitoring of rSO2 by NIRS did not show a corresponding decrease in cerebral oxygenation. As the patients exhibited decreased cognitive functions after CPB, increases in jugular venous LP ratio may be a sensitive indicator of impending cerebral damage.

Shoulder Pain After Thoracic Surgery: Type and Time Course, a Prospective Cohort Study.

OBJECTIVES: To study the time course of ipsilateral shoulder pain after thoracic surgery with respect to incidence, pain intensity, type of pain (referred versus musculoskeletal), and surgical approach. DESIGN: Prospective, observational cohort study. SETTING: Odense University Hospital, Denmark. PARTICIPANTS: Sixty patients for major lung resection. INTERVENTIONS: Postoperative observation of ipsilateral shoulder pain. MEASUREMENTS AND MAIN RESULTS: Postoperative numeric rating scale score of shoulder pain and thoracic pain and postoperative examination of the sites of shoulder pain for musculoskeletal involvement (muscle tenderness on palpation and movement) with follow-up 12 months after surgery. Clinically relevant pain was defined as a numeric rating scale score>3. Of the 60 patients included, 47 (78%) experienced ipsilateral shoulder pain, but only 25 (42%) reported clinically relevant shoulder pain. On postoperative day 4, 19 patients (32%) still suffered shoulder pain, but only 4 patients (7%) had clinically relevant pain. Four patients (8%) still suffered shoulder pain 12 months after surgery. In 26 patients (55%), the shoulder pain was classified as referred versus 21 patients (45%) who suffered shoulder pain of the musculoskeletal type. Shoulder pain of the musculoskeletal type was significantly more intense (p = 0.0008) than referred shoulder pain. CONCLUSION: Only a subset of patients has clinically relevant shoulder pain after postoperative day 2. Chronic shoulder pain is a minor problem after lobectomy and previously may have been overestimated. Ipsilateral shoulder pain of the musculoskeletal type is more intense than referred ipsilateral shoulder pain.

The immune response is affected for at least three weeks after extensive surgery for ovarian cancer.

INTRODUCTION: The treatment of women with ovarian cancer in advanced stages consists of extensive surgery followed by chemotherapy initiated three weeks after surgery. In this study, selected immune parameters were investigated to elucidate when the immune system is normalised following the operation. METHODS: Ten women undergoing extensive surgery for ovarian cancer were compared with a control group of ten women undergoing abdominal hysterectomy for a benign diagnosis. Blood samples were collected over a period of 21 days post-operatively. The levels of interleukin-6, interleukin-8, interleukin-10 and the activity and total frequency of natural killer cells were measured. RESULTS: Interleukin-6 and interleukin-10 were significantly elevated immediately after the operation and also after 21 days. The total population of natural killercells and the total activity were reduced. The total activity of natural killer-cells did not normalise within 21 days. CONCLUSIONS: The level of the cytokines interleukin-6 and interleukin-10 is increased 21 days after the operation, and the function of natural killer cells is not normalised at 21 days after surgery. FUNDING: The study received funding from Odense University Hospital Free Research Fund. TRIAL REGISTRATION: not relevant.

A technique for continuous bedside monitoring of global cerebral energy state.

BACKGROUND: Cerebral cytoplasmatic redox state is a sensitive indicator of cerebral oxidative metabolism and is conventionally evaluated from the extracellular lactate/pyruvate (LP) ratio. In the present experimental study of global cerebral ischemia induced by hemorrhagic shock, we investigate whether the LP ratio obtained from microdialysis of cerebral venous blood may be used as a surrogate marker of global cerebral energy state. METHODS: Six female pigs were anesthetized and vital parameters were recorded. Microdialysis catheters were placed in the left parietal lobe, the superior sagittal sinus, and the femoral artery. Hemorrhagic shock was achieved by bleeding the animals to a mean arterial pressure (MAP) of approximately 40 mmHg and kept at a MAP of about 30-40 mmHg for 90 min. The animals were resuscitated with autologous whole blood followed by 3 h of observation. RESULTS: The LP ratio obtained from the intracerebral and intravenous catheters immediately increased during the period of hemorrhagic shock while the LP ratio in the arterial blood remained close to normal levels. At the end of the experiment, median LP ratio (interquartile range) obtained from the intracerebral, intravenous, and intra-arterial microdialysis catheters were 846 (243-1990), 309 (103-488), and 27 (21-31), respectively. There was a significant difference in the LP ratio obtained from the intravenous location and the intra-arterial location (P < 0.001). CONCLUSIONS: During cerebral ischemia induced by severe hemorrhagic shock, intravascular microdialysis of the draining venous blood will exhibit changes of the LP ratio revealing the deterioration of global cerebral oxidative energy metabolism. In neurocritical care, this technique might be used to give information regarding global cerebral energy metabolism in addition to the regional information obtained from intracerebral microdialysis catheters. The technique might also be used to evaluate cerebral energy state in various critical care conditions when insertion of an intracerebral microdialysis catheter may be contraindicated, e.g., resuscitation after cardiac standstill, open-heart surgery, and multi-trauma.